2-Carbalkoxy-2&#39;-aminocarbonyldiphenyl sulfides

ABSTRACT

Compounds, pharmaceutical preparations containing same, and method of treating depression in mammals, the compounds being of the formula I ##STR1## or an acid addition salt thereof, particularly a pharmacologically or pharmaceutically acceptable salt thereof, where R and R 1  are the same or different and are each hydrogen or lower alkyl, or R and R 1  taken together are (CH 2 ) X  where X is 4 or 5, or NRR 1  is ##STR2## where Y is 3 or 4 and R 3  is hydrogen or lower alky, or NRR 1  is ##STR3## where R 2  is hydrogen or lower alkyl, in the above lower alkyl has 1 to 4 carbons and may be straight or branched and n and m are the same or different and are 1, 2, or 3.

This is a division of application Ser. No. 597,697 filed July 21, 1975,now U.S. Pat. No. 3,997,540.

The present invention relates to substituted diphenyl sulfides which areuseful in the treatment of mammals such as mice, dogs, rats or humans(man) suffering from a depressed state or condition.

In particular the present invention is directed to compounds representedby the formula I ##STR4## or an acid addition salt thereof where R andR¹ are the same or different and are each hydrogen or lower alkyl or Rand R¹ taken together are (CH₂)_(X) where X is 4 or 5 or NRR¹ is##STR5## where R² is hydrogen or lower alkyl or NRR¹ is ##STR6## where Yis 3 or 4 and R³ is hydrogen or lower alkyl, in the above lower alkylhas 1 to 4 carbon atoms and may be straight or branched and n and m arethe same or different and are each 1, 2 or 3.

Of the compounds of formula I those which are preferred are those inwhich NRR¹ are the same or different and are hydrogen or lower alkyl of1 to 4 carbons. The most preferred of formula I are those in which NRR¹are the same or different and are hydrogen or lower alkyl of 1 to 4carbons and n and m= 1.

In particular the salts should be pharmaceutically acceptable acidaddition salts when used for administration to a mammal. However itshould be understood that toxic salts may conveniently be converted topharmaceutically acceptable salts in a conventional exchange reaction,double decomposition reaction or by other known methods.

In addition acid addition salts e.g. toxic and non-toxic (i.e.pharmaceutically acceptable salts) are useful in the preparation ofuseful compounds known in the art. The compounds of formula I possessvaluable properties as antidepressants when tested by standardtechniques used in the art for determining antidepressant activity, forexample the tetrabenzene-induced sedation test in the rat. The compoundsof this invention are also notable for their low toxicity. Of thecompounds of formula I the following is especially preferred for itshigh antidepressant activity.

2-N,N-Dimethylaminomethyl-2'-hydroxymethyldiphenyl sulfide m.p.161°-163° C.

Other compounds of notable activity are as follows:

2-N-Methylaminomethyl-2'-hydroxymethyldiphenyl sulfice m.p. 217°-219° C.

2-aminomethyl-2'-hydroxymethyldiphenyl sulfide m.p. 188°-190° C.

2-n,n-diethylaminomethyl-2'-hydroxymethyldiphenyl sulfide m.p. 148°-150°C.

2-n-ethylaminomethyl-2'-hydroxymethyldiphenyl sulfide m.p. 182°-183° C.

Other compounds of particular interest include those of formula I whichare as follows:

    ______________________________________                                        NRR.sup.1 (where n = m = 1)                                                   ______________________________________                                        N(CH.sub.2).sub.4  m.p. 190 - 192° C                                   N(CH.sub.2).sub.5  m.p. 172 - 173° C                                    ##STR7##          m.p. 243 - 244° C                                   ______________________________________                                    

In the above m.p.=melting point

The compounds of this invention may be synthesized by any of a number ofmethods which may be classified in terms of the final step as follows:

(a) Formation of the sulfide bridge [Methods (1) and (2)].

(b) Reduction of --CO₂ H(Alk) to --CH₂ OH and/or --CONRR' to --CH₂ NRR'[Methods (3)-(7) and (15)].

(c) Replacement of a leaving group on one of the methylene substituentsby OH or NRR' [Methods (8) and (9)].

(d) Alkylation of the --NHR [Methods (10)-(12)].

(e) Reduction of a sulfone (--SO₂ --) or sulfoxide (--SO--) bridge to asulfide (--S--) bridge [Method (13)].

(f) Reduction of ##STR8## when neither R nor R¹ is hydrogen [Method(14)].

Abbreviations used herein: Alk is lower alkyl; LAH is lithium aluminumhydride; DMA is dimethylacetamide; DMF is dimethylformamide; DMSO isdimethylsulfoxide; red. is reducing agent.

The above classifications may be exemplified by the following methods:##STR9##

Reaction conditions: Anhydrous; suitable reaction temperature about roomtemperature to about the boiling point of the solvent; other suitablesolvents include DMF and DMSO. ##STR10##

Reaction conditions: Same as Method (1). ##STR11##

Reaction conditions: Same as Method (1). ##STR12##

Reaction conditions: May be carried out neat (i.e. with excess SOCl₂ assolvent) or in a non-reactive solvent such as benzene, toluene,methylene chloride, etc.); temperature about room temperature to theboiling point of the solvent. ##STR13##

Reaction conditions: May be conveniently carried out in aqueous mediumusing sodium hydroxide to neutralize the hydrogen chloride formed.Organic solvents such as ether, toluene, etc. may be used; alcohol mayalso be used provided the acid chloride is added to an alcoholicsolution of the amine. An excess of the amine or a tertiary amine suchas triethylamine may be used to neutralize the hydrogen chloride formedif desired. Temperatures used are generally low, from 0° C to about roomtemperature but may be higher if desired. ##STR14##

Reaction condition: Generally carried out in ether (e.g. diethyl etheror tetrahydrofuran) solution and at room temperature, but slightlyelevated temperatures could be used. ##STR15##

Reaction conditions: Same as Method (1). May also be carried out inaqueous sodium hydroxide at elevated temperatures. May conveniently becarried out in the presence of copper and potassium carbonate in aqueousmedium in a bomb at elevated temperature, e.g. 120° C. ##STR16##

Reaction conditions: Anhydrous; equimolar amount of alcohol used;solvents such as dioxane, DMSO suitable.

(II) may be converted into (I) as in steps (b), (c) and (d) of method(3). ##STR17##

Reaction conditions: Same as Method (1) ##STR18##

Reaction conditions: Conveniently carried out in aqueous alcohol atelevated temperatures. ##STR19##

Reaction conditions: Same as Method (3) step (b). ##STR20##

Reaction conditions: Same as Method (3) step (c). ##STR21##

Reaction conditions: Same as Method (3) step (d) ##STR22##

Reaction conditions: May be carried out in aqueous or alcoholic solventsat temperatures ranging from about room temperature to reflux. Anhydroussolvents, e.g. xylene, at elevated temperatures may also be used.##STR23##

Reaction conditions: Same as Method (1)

(VII) may be converted into (I) as in Method (5) steps (c) ff. ##STR24##

Reaction conditions: X is a leaving group displacable by an amine, suchas halide (esp. bromide), tosylate, mesylate, or azide. An inert solventsuch as e.g. toluene, dioxane, acetonitrile and temperatures from aboutroom temperature to reflux may be used. ##STR25##

Reaction conditions: X is as defined in Method (8) plus carboxylicesters, dilute alkali in aqueous solution such as e.g. water,acetonitrile, DMF at elevated temperatures are generally used. ##STR26##

Reaction conditions: Same as Method (1) ##STR27##

Reaction conditions: Same as Method (3) step (d). ##STR28##

Reaction conditions: Generally same as Method (3) step (c) except thatif a base is used to neutralize the hydrochloric acid formed it shouldbe an organic base. R⁴ is lower alkyl. ##STR29##

Reaction conditions: Same as Method (3) step (d).

(XI) may be further alkylated by repeating steps (c) and (d) to providethe teriary amino compound. ##STR30##

Reaction conditions: Generally carried out in aqueous, alcoholic orpolar aprotic solvents such as acetonitrile, DMF, DMSO at elevatedtemperatures. Other reducing agents (than the formic acid) which may beused include formic acid derivatives such as ammonium formate and metalhydride derivatives such as NaBH₃ CN. ##STR31##

Reaction conditions: Same as Method (11) ##STR32##

Reaction conditions: Z is 1 or 2, reducing agents such astriphenylphosphine or metal hydride derivatives such as LAH may be usedin non-reactive organic solvents such as ethers.

Compounds (XII) may be prepared by oxidizing the diphenyl sulfideintermediates of Method (8) or strong acid addition salts, e.g.hydrochloride salts, of the diphenyl sulfide intermediates of Method (9)by conventional methods (e.g. perbenzoic acid in toluene at roomtemperature) followed by the replacement reactions described in thesemethods.

The diphenylsulfide intermediates of Methods (3)-(7) may be oxidized asabove to give the corresponding sulfoxide or sulfone intermediates whichmay then be carried thru the remaining steps of these methods giving inthe final step simultaneous reduction of the sulfone or sulfoxide moietyand the amide and/or ester (or acid) moieties. ##STR33##

Reaction conditions: Reducing agents and solvents as in Method (13) aresuitable.

The compounds (XIII) may be prepared by oxidation of the diphenylsulfideintermediates of Method (9) with e.g. NaIO₄.

Similarly, compounds having both sulfoxide (or sulfone) and N-oxidemoieties may be prepared by nonspecific oxidation (e.g. usingm-chloroperbenzoic acid in toluene at room or elevated temperature) ofthe intermediates of Method (a). These may be converted into compoundsof formula (I) by replacing the leaving group with OH as in Method (9)and then simultaneously reducing the sulfoxide (sulfone) and N-oxidegroups using reaction conditions as in Method (13). ##STR34##

Reaction conditions: Same as Method (1) ##STR35##

Reaction conditions: Same as Method (3) step (d).

The preferred antidepressant dosage for parenteral administration of acompound of formula (I) (estimated as the base) is about 5 mg/kg to 50mg/kg of mammal body weight, and the most preferred dosage being 15mg/kg to 35 mg/kg of mammal body weight.

For the oral or rectal mode of administration, the preferredantidepressant dosage of a compound of formula (I) (estimated as thebase) is about 10 mg/kg to 100 mg/kg of mammal body weight while themost preferred dosage (estimated as the base) is about 30 mg/kg to 70mg/kg of mammal body weight. A compound of formula (I), or an acidaddition salt thereof, is preferably administered four times dailyalthough the number of daily administrations of the medication may varyaccording to the patient (mammal) being treated, and the exercise of thephysician's discretion.

For the treatment of depression in humans, the preferred unit dosage ofa compound of formula (I) or an acid addition salt thereof (as the base)for oral administration, or administration as a suppository, is about 15milligrams to 500 milligrams with the more preferred unit dosage beingabout 100 milligrams to 300 milligrams, and the most preferred unitdosage being about 125 milligrams to 250 milligrams. All the above dosesare given in terms of the weight of a compound of formula (I) in theform of its base, but as will be appreciated from the foregoinginformation, it is preferably administered in the form of apharmaceutically acceptable acid addition salt thereof.

A compound of formula (I) or pharmaceutically acceptable salts thereofmay be presented as an oral unit preparation (for example as a cachet,tablet or capsule) containing one or more pharmaceutically acceptablecarriers which may take the form of solid diluents such as lactose,cornstarch, micronized silica gel, or merely the capsule shell as wellas other excipients well known in the art for this purpose.

According to the present invention there is provided a compound of theformula (I) and a pharmaceutically acceptable salt thereof.

According to the present invention, in yet another aspect, there isprovided a pharmaceutical composition (preferably in unit dosage form)comprising a compound of formula (I) (or a pharmaceutically acceptablesalt thereof) together with a pharmaceutically acceptable carrier.Conveniently the compound of formula (I) or its acid addition saltcomprises from 5 to 95% by weight of the composition.

According to the present invention in yet another aspect there areprovided methods of synthesizing compounds of formula (I) comprising theapplication of methods specified above those apparent therefrom for thepreparation of diphenyl sulphide of formula I.

According to still a further aspect of the present invention, there isprovided a method of treating a depressed state in mammals such ashumans, mice, rats, dogs, etc., which comprises the administration of anantidepressant effective non-toxic amount (dose), preferably in a unitdosage form, of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

The compounds of formula (I) (the active ingredients) or thepharmaceutically acceptable salt thereof is preferably administered inunit dosage form to the mammal being treated.

The compounds of this invention may be administered orally, parenterallyor rectally.

A pharmaceutical composition containing a compound of formula (I), or apharmaceutically acceptable salt thereof, may be presented in discreteunits such as tablets, capsules, ampoules or suppositories, eachcontaining an effective antidepressant non-toxic amount of the compound.

A compound of formula (I) or a pharmaceutically acceptable salt thereofmay be presented for rectal use as a suppository with the usualpharmaceutically acceptable carriers such as cocoa butter, and may bepresented for parenteral use as an ampoule of a sterile solution orsuspension with water or other pharmaceutically acceptable liquid as thecarrier therefor, or as an ampoule of a sterile powder for dilution witha pharmaceutically acceptable liquid.

It should be understood that in addition to the aforementionedingredients, the pharmaceutical compositions of this invention mayinclude one or more of additional ingredients such as diluents, buffers,flavouring agents, binders, surface active agents, thickeners,lubricants, preservatives, and the like. The formulations may beprepared by admixture of the ingredients, and, if necessary, shaping theresulting mass, and filling into suitable containers.

The compound of formula I is preferably presented for use in thetreatment of depressed states as a pharmaceutically acceptable salt.Examples of some of the pharmaceutically acceptable salts which can beutilized are salts of the following inorganic or organic acids:hydrochloric, sulfuric, phosphoric, toluenesulphonic, maleic, fumaric,tartaric, citric, acetic, pamoic, and succinic.

Acid addition salts may also be formed from acids such as nitric andoxalic.

In addition the compounds of this invention where R and R¹ in formula Iare the same or different and each is lower alkyl or hydrogen and n═ m═1 are useful as intermediates in the preparation of compounds of thegeneral formula of U.S. Pat. No. 3,803,143 by treating same with PBr₃ inchloroform at room temperature.

For example where R is H and R¹ is lower alkyl, the compounds aredirectly converted to the compounds of U.S. Pat. No. 3,803,143.

2-Hydroxymethyl-2'-methylaminomethyldiphenyl sulfide was treated withPBr₃ in chloroform at room temperature and 6-N-methyl-5H,7H-dibenzo[b,g]-(1,5)thiazocine was obtained (Example 20 U.S. Pat. No.3,803,143).

Where R and R¹ are hydrogen, the same procedure may be followed and theamine is then alkylated by formaldehyde/formic acid as is conventional.

Where R and R¹ are both lower alkyl, a quaternary salt is formed andthereafter one of the alkyls is displaced by hydride e.g. lithiumaluminum hydride in a conventional manner.

The present invention is also directed to intermediates of the formula Aand B which are converted as disclosed herein to the compounds I.##STR36##

In the above ALK is lower alkyl of 1 to 4 carbons and R and R¹ are asdefined in Formula I. In particular ALK is preferably ethyl.

EXAMPLE 1 2-Carbethoxy-2'-carboxydiphenyl sulfide

2,2'-Dicarbethoxydiphenyl sulfide (120 g.) was added to a solution ofpotassium hydroxide (22 g.) in one liter of ethanol and stirred at roomtemperature for 4 days. It was acidified with concentrated hydrochloricacid, filtered. The product obtained on concentration of the filtrate todryness was partitioned between ether and five percent sodiumbicarbonate. The mixture of diacid and half ester-acid obtained onacidification was triturated with warm benzene to separate the insolublediacid. The product was precipitated by the addition of n-hexane to thebenzene extract. Recrystallization from acetone/n-hexane mixtures gave2-carboxy-2'-carbethoxydiphenyl sulfide (43.0 g., 37%), m.p. = 122°-23°C.

EXAMPLE 2 2-Carbethoxy-2'-dimethylaminocarbonyldiphenyl sulfide

The half ester-acid chloride (32.0 g.) obtained by the reaction of2-carbethoxy-2'-carboxydiphenyl sulfide (30.2 g.) with excess thionylchloride was dissolved in 150 ml. of dry dioxane and added to an excessof ice-cold solution of dimethylamine in dry dioxane. The solution wasstirred at room temperature for one hour, acidified, filtered. Theresidue obtained by concentrating the filtrate in vacuo was dissolved in250 ml. of chloroform and washed successively with 10% acid, 5%bicarbonate and water. On drying and subsequent removal of the solvent,32.0 g. (97%) of the amido-ester was obtained as an orange colored oil.

EXAMPLES 3 AND 4

The following were prepared by the procedure of Example 2.

2-Carbethoxy-2'-aminocarbonyldiphenyl sulfide

m.p. = 126° -29° C (80% yield)

2-Carbethoxy-2'-methylaminocarbonyldiphenyl sulfide

m.p. = 92° -94° C (96% yield)

EXAMPLE 5 2-Hydroxymethyl-2'-dimethylaminomethyldiphenyl sulfide .HCl

To a slurry of lithium aluminum hydride (15.2 g) in 800 ml. oftetrahydrofuran, at room temperature, was added a solution of2-carbethoxy-2'-dimethylaminocarbonyldiphenyl sulfide 32.9 g. in 150 mlof tetrahydrofuran and the mixture was stirred at room temperature for18 hours. The reaction was worked up in the usual manner and the freebase was obtained as an yellow oil. The hydrochloride salt wascrystallized from ethanol/ether mixtures to give 19.0 g. (60% yield) of2-hydroxymethyl-2'-dimethylaminomethyldiphenyl sulfide, m.p. 162° -64°C.

EXAMPLES 6 AND 7

The following were prepared by the procedures of Examples 2 and 5.

2-Hydroxymethyl-2'-aminomethyldiphenyl sulfide .HCl

m.p. = 188° -89° C (60% yield)

2-Hydroxymethyl-2'-methylaminomethyldiphenyl sulfide .HCl

M.P. = 218° -20° C (90% yield)

EXAMPLE 8 2,2'-Dicarboxy diphenyl sulfide

2-Bromobenzoic acid (40.0 g.) and 2-mercaptobenzoic acid (32.0 g) weredissolved in 140 ml of water, containing 56 g. of potassium carbonate.Upon dissolution, 13.0 g of powdered Cu was added. This homogeneoussolution was transferred to a stainless steel bomb and heated at 130°-140° for 3 hr. Bomb was cooled; contents were filtered and the filtrateacidified with conc. HCl. Filtration yielded 52.8 g (97%) of2,2'-dicarboxydiphenyl sulfide, m.p. 225° -30° C [Lit. m.p. 233° , C. A.54, 9815d (1960)].

EXAMPLE 9 2,2'-Dicarbethoxydiphenyl sulfide

2,2'-Dicarboxydiphenyl sulfide (54.8 g., 0.20 mol.) was treated withexcess thionyl chloride (100 ml.) at 60° C until a clear solution wasobtained. The excess thionyl chloride was removed under reducedpressure. The resulting solid was then treated with 200 ml. of EtOH atreflux for 30 min. The ethanol solution was added to 1 liter of icewater. The diester was filtered and dried, yielding 62.0 g (90%), m.p.56° -57° [lit. m.p. 58° -59° , C. A. 54, 9815d 13.0 1960)].

EXAMPLE 10 2-Carbethoxy-2'-N-methylpiperazinocarbonyldiphenyl sulfide

To the solution of 3.6 g. of 2-carbethoxy-2'-chlorocarbonyldiphenylsulfide in 100 ml. of acetonitrile, at room temperature, was added asolution of 11.6 g. of N-methylpiperazine in 50 ml. of triethylamine.After 3 hours of stirring the solvent was removed and the residue wastaken up in 250 ml chloroform. It was washed successively with 10%hydrochloric acid, sodium bicarbonate and water. On concentration 13.0g.(94% yield) of an orange oil was obtained.

EXAMPLE 11 2-Hydroxymethyl-2'-N-methylpiperazinomethyldiphenyl sulfide.HCl

To a slurry of 4.0 g. of lithium aluminum hydride in 500 ml. oftetrahydrofuran, at room temperature, was added a solution of 12.6 g. of2-carbethoxy-2'-N-methylpiperazinocarbonyldiphenyl sulfide in 100 ml. oftetrahydrofuran. The mixture was stirred at room temperature for 18hours. The reaction was worked up in the usual manner to afford 9.2 g.(85%) of the free base as a yellow oil. The hydrochloride salt wascrystallized from 50% aqueous EtOH to afford 9.0 g. (65%) of the productas a dihydrate, m.p. 243° -44° C.

EXAMPLE 12 2-Carbethoxy-2'-pyrrolidinocarbonyldiphenyl sulfide

To the stirred solution, at room temperature, of 4.8 g. of pyrrolidinein 50 ml. of triethylamine was added 20 g. of2-carbethoxy-2'-chlorocarbonyl diphenyl sulfide in 150 ml. of dryacetonitrile. After stirring for 3 hours the solvents were removed invacuo and the residue taken up in 250 ml. of chloroform. It wassuccessively treated with 10% hydrochloric acid, 5% bicarbonate andwater. After drying, concentration and recrystalization fromacetone-hexane mixtures 17.0 g. (72% yield) of pure product, m.p. 117°-19° C, was obtained.

EXAMPLE 13 2-Carbethoxy-2'-piperidinocarbonyldiphenyl sulfide

Following the procedure of Example 12,2-carbethoxy-2'-piperidinocarbonyldiphenyl sulfide, m.p. 111° -13° C,was prepared in 75% yield.

EXAMPLE 14

To the slurry of 13.3 g. of lithium aluminum hydride in 800 ml. oftetrahydrofuran was added a solution of 25 g. of2-carbethoxy-2'-pyrrolidinocarbonyldiphenyl sulfide in 150 ml. oftetrahydrofuran under nitrogen atmosphere at room temperature. It wasstirred for 18 hours. The reaction mixture was decomposed by the usualprocedure and the hydrochloride salt of the base, m.p. 190° -92° C, 17.0g. (73% yield) was obtained. The compound obtained was2-hydroxymethyl-2'-pyrrolidinomethyldiphenyl sulfide .HCl

EXAMPLE 15A 2-Hydroxymethyl-2'piperidinomethyldiphenyl sulfide .HCl

M.P. 172° -73° C

Following the procedure of Example 12,2-hydroxymethyl-2'-piperidinomethyldiphenyl sulfide was prepared in thehydrochloride salt, m.p. 172° -173° C, in 80% yield.

EXAMPLE 15 Tablet Formulation

150 mg. of 2-N,N-Dimethylaminomethyl- 2'-hydroxymethyl diphenyl sulfidehydrochloride

85 mg. Lactose

50 mg. Cornstarch

10 mg. Micronized Silica Gel

5 mg. Polyvinyl pyrrolidone

Procedure

The lactose, cornstarch and salt is mixed together and granulated with abinder, polyvinyl pyrrolidone in alcoholic solution, to form granules.The granules were passed through a 16-20 mesh screen, then air dried,lubricated with micronized silica gel and compressed into tablets. Afilm coating could then have been applied if desired.

EXAMPLE 16 Capsule Formulation

150 mg. of 2-N-methylaminomethyl-2'-hydroxymethyl diphenyl sulfidehydrochloride is mixed with 125 mg. of lactose and 125 mg. ofcornstarch. The mixture was filled into a two piece hard gelatincapsule.

EXAMPLE 17 Parenteral Solution

150 mg. of 2-N,N-diethylaminomethyl-2'-hydroxymethyl diphenyl sulfidehydrochloride is dissolved in sterile water U.S.P. to make 1 ml. Amulti-dose preparation may include bacteriostats such a 0.2 to 0.5% w/vof phenol.

EXAMPLE 18 Suppository

150 mg. of 2-aminomethyl-2'-hydroxymethyldiphenyl sulfide hydrochlorideis mixed with 205 mg. of softened or melted cocoa butter, andsuppositories were formed by chilling and shaping in molds.

EXAMPLE 19 Capsule

200 mg. of 2-N-ethylaminomethyl-2'-hydroxymethyl diphenyl sulfidehydrochloride is placed in a two piece hard gelatin capsule.

EXAMPLE 20 Anti-Tetrabenazine Test

Sprague-Dawley male rats weighing approximately 180 gm. were grouped sixper cage. Compounds of Formula I as the hydrochloride salt in saline areinjected i.p. thirty minutes prior to the administration oftetrabenazine, 20 mg/kg, i.p. Animals were scored according to themethod of Sulser and Soroko, Psychopharmacology 8, 191 (1965).

    ______________________________________                                        RESULTS                                                                                       Effective Anti-Tetrabenzine                                                   Activity in the Rat                                           NRR' where n=m=1                                                                              (mg/kg i.p.)*                                                 ______________________________________                                        NH.sub.2        25                                                            N(CH.sub.3)H    12.5                                                          N(CH.sub.3).sub.2                                                                             12.5                                                          N(C.sub.2 H.sub.5).sub.2                                                                      25                                                            ______________________________________                                         *Equal to a standard desmethylimipramine at 5 mg/kg i.p. similarly            injected into rats as above.                                             

6-Methyl-5H,7H-dibenzo[b,g][1,5]thiazocine

To a solution of 19.6 g (0.076 mol) of 2-hydroxymethyl-2'-methylaminomethyldiphenyl sulfide in 1 l. of chloroform was added asolution of 13.5 g (0.05 mol) of phosphorus tribromide in 100 ml. ofchloroform under an atmosphere of N₂ while keeping the reaction vesselimmersed in an ice bath. This solution was stirred for 2 hours at icebath temperatures; then 17 hours at room temperature. This cloudysolution was refluxed for 2 hours, cooled, 500 ml. of ice H₂ O added.Potassium carbonate was added until the aqueous phase was alkaline. Theorganic layer was separated; the basic aqueous layer was extracted threetimes with 200 ml. portions of chloroform. The chloroform extracts werecombined and dried over anhydrous potassium carbonate. Removal ofchloroform under reduced pressure gave a yellow oil. This oil wastriturated with ether with the simultaneous precipitation of a tansolid, filtered and the ether removed to get 16.9 g (92%) of a lowmelting solid. The amine was converted to its hydrochloride salt viaethereal·HCl. Recrystallization from ethanol-acetone afforded a whitesolid: m.p. 217° -219° .

What is claimed is:
 1. The compound of the formula ##STR37## where R andR¹ are the same or different and are each hydrogen or lower alkyl andALK is alkyl of 1 to 4 carbon atoms, in the above lower alkyl has 1 to 4carbon atoms.
 2. The compound of claim 1 where R¹ and R is H, R¹ and Rare methyl, R¹ and R are ethyl, R is H and R¹ is methyl, or R is H andR¹ is ethyl.
 3. The compound of claim 1 where R¹ and R=methyl.
 4. Thecompound of claim 1 where R¹ is methyl and R is hydrogen.
 5. Thecompound of claim 1 in which ALK is ethyl.
 6. The compound of claim 2 inwhich ALK is ethyl.
 7. The compound of claim 1 which is2-carbethoxy-2'-dimethylaminocarbonyldiphenylsulphide.
 8. The compoundof claim 1 which is 2-carbethoxy-2'-aminocarbonyldiphenylsulphide. 9.The compound of claim 1 which is2-carbethoxy-2'-methylaminocarbonyldiphenylsulphide.
 10. The compound ofclaim 1 which is 2,2'-dicarbethoxydiphenylsulphide.